The adenosine A₁ receptor (A₁R) is a promising therapeutic target for non-opioid analgesic agents to treat neuropathic pain^1,2. However, development of analgesic orthosteric A₁R agonists has failed because of a lack of sufficient on-target selectivity as well as off-tissue adverse effects³. Here we show that [2-amino-4-(3,5-bis(trifluoromethyl)phenyl)thiophen-3-yl)(4-chlorophenyl)methanone] (MIPS521), a positive allosteric modulator of the A₁R, exhibits analgesic efficacy in rats in vivo through modulation of the increased levels of endogenous adenosine that occur in the spinal cord of rats with neuropathic pain. We also report the structure of the A₁R co-bound to adenosine, MIPS521 and a G_i2 heterotrimer, revealing an extrahelical lipid–detergent-facing allosteric binding pocket that involves transmembrane helixes 1, 6 and 7. Molecular dynamics simulations and ligand kinetic binding experiments support a mechanism whereby MIPS521 stabilizes the adenosine–receptor–G protein complex. This study provides proof of concept for structure-based allosteric drug design of non-opioid analgesic agents that are specific to disease contexts.

腺苷 A ₁受体 (A ₁ R) 是非阿片类镇痛剂治疗神经性疼痛的一个有前景的治疗靶点^1,2 。然而，由于缺乏足够的靶向选择性以及组织外不良反应，镇痛正位 A ₁ R 激动剂的开发失败了³ 。在这里，我们表明，[2-氨基-4-(3,5-双(三氟甲基)苯基)噻吩-3-基)(4-氯苯基)甲酮] (MIPS521)，A ₁ R的正变构调节剂，表现出通过调节神经性疼痛大鼠脊髓中内源性腺苷水平的增加，在大鼠体内发挥镇痛功效。我们还报告了与腺苷、MIPS521 和 G _i2异三聚体共结合的 A ₁ R 的结构，揭示了一个面向脂质去垢剂的螺旋外变构结合口袋，涉及跨膜螺旋 1、6 和 7。分子动力学模拟和配体动力学结合实验支持 MIPS521 稳定腺苷-受体-G 蛋白复合物的机制。这项研究为特定于疾病背景的非阿片类镇痛剂的基于结构的变构药物设计提供了概念证明。